Abstract 3744: Multiple endocrine-resistant breast cancer cell lines retain ER and sensitivity to endocrine therapy

Endocrine therapy is the standard of care for breast cancer expressing estrogen receptor (ER), which occurs in 70% of patients. Unfortunately, acquired or de novo resistance to endocrine therapy is observed in up to 50% of patients, leaving a significant portion of patients with insufficient treatment options. Endocrine-resistance, usually defined as resistance to tamoxifen and aromatase inhibitor (AI) therapy, can also include resistance to selective estrogen receptor degraders (SERDs), since these also target ER. Since multiple mechanisms contribute to resistance, development of multiple resistant cell lines is needed for drug discovery and to identify characteristics that may suggest susceptibility to alternative and combination therapies. We have developed 5 stable, endocrine-resistant cell lines from a parent MCF-7 cell line, which all retain ER: one of these cell lines, MCF-7:CFR is resistant to the SERD fulvestrant. Clinical metastatic breast cancers that have gained endocrine resistance are overwhelmingly ER+. In addition to ER, progesterone receptor (PR) and glucocorticoid receptor (GR) status of these lines was assessed, and correlated with the response of these cells in culture to four classes of endocrine therapeutics: SERDs, selective ER modulators (SERMs), and selective human ER partial agonists (ShERPAs). Growth of all 5 cell lines was endocrine independent, indicating resistance to AI therapy. Two of the ER+, PR- cell lines were most resistant to the spectrum of endocrine therapies, but these cell lines both showed sensitivity to ShERPAs, especially in combination with non-endocrine targeted therapies, such as the PI3K inhibitor, alpelisib. Paradoxically, all endocrine-resistant cell lines responded to at least one of the endocrine therapies tested, demonstrating that if ER is not lost in the metastatic state, it remains a vulnerability suitable for therapeutic targeting. Citation Format: Lauren M. Gutgesell, Rui Xiong, Jiong Zhao, Huiping Zhao, Debra A. Tonetti, Gregory R. Thatcher. Multiple endocrine-resistant breast cancer cell lines retain ER and sensitivity to endocrine therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3744.